Preparation of arylphosphines

ABSTRACT

The present invention pertains to a process for the preparation of an arylphosphine of the formula R 1 OC—Ar—PR 2 R 3  wherein Ar is aryl or heteroaryl; R 1  is an alkoxy or amine group; and R 2  and R 3  are each any organic group; and each of the respective groups may optionally be substituted with any non-interfering group; which comprises the reaction of a sulfonyloxy compound of the formula R 1 OC—Ar—OSO 2 R 4  wherein R 4  is alkyl, haloalkyl, perhaloalkyl, aryl, aralkyl or alkaryl, with a phosphine of the formula HPR 2 R 3 , in a solvent and in the presence of a palladium catalyst and a base. The arylphosphine can then readily be converted to a chiral phosphine ligand.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a U.S. national stage application of Internationalpatent Application No. PCT/GB99/02065, filed Jun. 30, 1999, which claimspriority from U.S. Provisional Application No. 60/096,174, filed Aug.11, 1998.

FIELD OF THE INVENTION

This invention relates to processes suitable for the large scalepreparation of arylphosphines. especially those useful as ligandprecursors or ligands in asymmetric allylic substitution catalysts.

BACKGROUND OF THE INVENTION

Chiral phosphine ligands such as (1) and (2)

and the opposite enantiomers thereof, have been shown to be effective inpalladium(0)-catalysed asymmetric allylic substitution reactions. For areview, see Trost and Van Vranken, Chem Rev. (1996) 96: 395. See alsoU.S. Pat. No. 5,739,396.

Such catalysts are eminently suitable for industrial applications,especially for the provision of chiral pharmaceutical intermediates suchas phthalimidovinyl glycinol, in high enantiomeric purity. For thispurpose, and in other industrial applications such as flavour andfragrance fine chemicals, the development of manufacturing processesrequires in turn large amounts of a ligand such as (1) or (2), e.g. inkilogram quantity or greater. Thus, there is a requirement for efficientand scaleable methods for synthesis of such ligands.

A key intermediate in the synthesis of these ligands is2-diphenylphosphino-1-naphthoic acid and derivatives thereof. Severalprocesses for the synthesis of arylphosphines from aryl triflates havebeen described in the literature.

For example, WO-A-9312260 and U.S. Pat. No. 5,739,396 disclose thereaction of trimethylsilyldiphenylphosphine, an aryl iodide andbis(benzonitrile)palladium dichloride in toluene at reflux.Trimethylsilyldiphenylphosphine is expensive and not readily available.This procedure gives only moderate yields (60%) and requires silicachromatography for purification of the product.Bis(benzonitrile)palladium dichloride is also expensive, and a highcatalyst loading is used (5 mol %).

Another known process comprises the reaction of an aryl triflate withchlorodiphenylphosphine, a reductant (zinc) and a nickel catalyst in DMFat 100° C.; see Ager et al, Chem. Commun. (1997) 2359. This proceduretypically requires a high catalyst loading (4-10 mol %) and can involveprolonged heating at reflux. The nickel catalyst is highly toxic and, aswell as considerations for operator safety and residue disposal,filtration through a plug of silica is typically required to remove thecatalyst.

Cai et al, J. Org. Chem. (1994) 59:7180-1, and U.S. Pat. No. 5,399,771disclose the preparation of BINAP using the appropriate aryl triflatewith diphenylphosphine. The preferred catalyst is nickel, palladiumcatalysis giving no reaction al all. Cai et al reports that DMF is theonly satisfactory solvent. A chelating phosphine was also present.

Gilbertson et al, J. Org. Chem. (1996) 61:2922-3, discloses thepalladium-catalysed conversion of aryl triflates, specifically tyrosinederivatives, to the corresponding aryl diphenylphosphines, by reactionwith diphenylphosphine. The solvent is DMSO. It is reported that thereaction does not take place in DMF, using palladium. The SupplementaryMaterial shows that 5 mol % of each of the catalyst Pd(OAC)₂ and1,4-bis(diphenylphosphino)butane, i.e. a chelating phosphine, are used.Isolation of pure aryl diphenylphosphine products requires conversion tothe corresponding phosphine sulfide, column chromatography anddesulfurization with Raney nickel.

Reaction of diphenylphosphine, a base, palladium catalyst and aryliodide (or bromide) also gives the corresponding triarylphosphine; seeWerd et al, J. Organomet. Chem. (1996), 522: 69. For the synthesis ofligand (1) or (2), however, a 2-iodo- or 2-bromo-1-naphthoic acidderivative is not readily accessible.

SUMMARY OF THE INVENTION

The present invention is based on the discovery of an alternativeprocess for preparing aryl phosphines, which allows the limitations ofthe prior art to be overcome. In particular, it has been discovered thatan aryl sulfonyloxy compound can participate in a cross-couplingreaction with diphenylphosphine and palladium catalyst, without many ofthe restrictions that prejudice the development of an efficient,scaleable and economical synthesis of phosphines. The invention concernsthe use of sulfonyloxy derivatives, readily prepared from the parentphenol, with a phosphine (HPR²R³), a base and palladium catalyst, in thefollowing reaction:

R¹OC—Ar—OSO₂R⁴—R¹OC—Ar—PR²R³

The group R¹ may be an alkoxy or amino group. The groups R² and R³ areany hydrocarbon group including, for example, aryl and alkyl. The groupR⁴ may be an aryl or alkyl group including those with halogensubstitution.

Each of the respective R groups may optionally be substituted with oneor more non-interfering group. Each such group may be of, for example,up to 20 C atoms.

One advantage of this invention is that no chelating phosphine isrequired. Another is that the solvent is not critical, thereby allowingthe use of common, easy-to-handle organic solvents such as toluene andacetonitrile. Without wishing to be bound by theory, these two factorsmay be linked.

A further advantage of the invention is that the catalyst loading neednot be especially high. For example, it is typically less than 1%, andoften less than 0.5% (mol % relative to sulfonate). In particular,one-to-one stoichiometries of the phosphine and sulfonyloxy compound maybe used, and with low catalyst loadings, for example 0.4 mol %,purification of the product is relatively simple.

In summary, this invention allows the aryl phosphine to be manufacturedeconomically on a large scale. Material of reproducible quality can bemanufactured in high yields.

DESCRIPTION OF THE INVENTION

Ar may represent any aromatic nucleus, mono or poly-cyclic, with orwithout hetero atoms such as N, O or S. Although the respective pointsof substitution of the COR¹ and PR²R³ groups on the nucleus are notthought to be critical, they are typically in 1,2, 1,3 or1,4-relationship on a benzene ring that is optionally otherwisesubstituted and/or fused to another ring or ring system. Thus, forexample, a starting material for use in the invention may have theformula

wherein R is any non-interfering substituent and/or represents a fusedring.

Ar is most preferably naphthyl. R¹ is preferably alkoxy, more preferablymethoxy.

A preferred embodiment of the present invention is a process for thepreparation of 2-diphenylphosphino-1-naphthoic acid and derivativesthereof, for example those compounds therein where R² and R³ are bothphenyl and R¹OC—Ar is 1-carboalkoxy-2-naphthyl. See the reaction shownin Example 1.

The preferred catalyst for this invention is a palladium (II) salt, morepreferably palladium (II) acetate. The preferred base is a tertiaryamine, more preferably triethylamine. The preferred groups for R⁴ areperfluoroalkyl groups, including trifluoromethyl and perfluoro-1-butyl.

Typically the reagents are heated together at reflux in an appropriatesolvent, for example toluene or acetonitrile, e.g. for approximately 16hours. The solvent can be much less volatile than DMSO, e.g. boilingbelow 125° C. Progress of the reaction may be monitored by TLC or takingaliquots for analysis by ¹H NMR or ³¹P NMR.

The following Examples illustrate the present invention. ThePreparations illustrate starting materials.

Preparation 1 Methyl 2-hydroxy-1-naphthoate

Dicyclohexyicarbodiimide (1.20 Kg, 5.8 mol, 1.1 eq) was addedportionwise over 4.5 hours to a cooled, mechanically-stirred slurry of2-hydroxy-1-naphthoic acid (1.00 Kg, 5.3 mol) in methanol (3 L) undernitrogen. The internal temperature was maintained between 10 and 15° C.during the addition. Once the addition was complete, the mixture wasallowed to warm to ambient temperature and stirred for 16 hours. Themethanol was removed under reduced pressure and the residue taken up inethyl acetate (5 L) and heated with stirring to 64° C. (internaltemperature) and then allowed to cool once again to ambient temperature.The mixture was filtered, and the solid washed with ethyl acetate (0.7L). The ethyl acetate solutions were combined and concentrated underreduced pressure. The residue (2.5 Kg) was recrystallised fromethanol-water (9:1, 3.3 L) and dried under vacuum at ambienttemperature. Yield 0.92 Kg, 85%

Preparation 2 Methyl 2-trifluoromethanesulfonyloxy-1-naphthoate

Trifluoromethanesulfonic anhydride (492 g, 1.74 mol, 1.1 eq) indichloromethane (0.5 L) was added over 1.5 hours to a suspension ofmethyl 2-hydroxy-1-naphthoate (319 g, 1.58 mol) and pyridine (330 ml,4.08 mol, 2.6 eq) in dichloromethane (1.7 L) maintained at an internaltemperature between −70 and −50° C., under nitrogen. Once the additionwas complete, the mixture was allowed to warm to ambient temperature andstirred for 16 hours, after which time all solids had dissolved. Methyltert-butyl ether (MTBE, 2.5 L) was added, causing precipitation. Thesolids were removed by filtration and washed with MTBE (0.5 L). The MTBEsolutions were combined and washed with 2 N HCl(aq) (0.3 L then 0.2 L),water (2×2.5 L) and brine (2 L). The organic layer was dried (MgSO₄),filtered and concentrated under reduced pressure. The residue wasdissolved in toluene (2.5 L) and washed with 1 N NaOH (aq) (0.5 L),water (2.5 L) and brine (1 L). The toluene solution was dried (MgSO₄),filtered and concentrated under reduced pressure. Initially a slightlybrown oil, the product crystallised on standing. Yield 438.5 g, 83%

Preparation 3 Methyl 2-trifluoromethanesulfonyloxysalicylate

Trifluoromethanesulfonic anhydride (28.4 mL, 169 mmol, 1.1 eq) was addedto a solution of methyl salicylate (20 mL, 154 mmol) and pyridine (31mL, 385 mmol, 2.5 eq) in dichloromethane (150 mL) maintained at aninternal temperature about −40° C., under nitrogen. Once the additionwas complete, the mixture was allowed to warm to ambient temperature andstirred for 16 hours. Toluene (150 mL) was added causing precipitation.The solids were removed by filtration and washed with toluene (20 mL).The organic solutions were combined and washed with 2 N HCl (aq) (2×50mL), water (100 mL), saturated aqueous sodium carbonate solution (100mL) and brine (100 mL). The organic layer was dried (MgSO₄), filteredand concentrated under reduced pressure. Yield 41.93 g, 96%

Preparation 4 Methyl 2-(perfluoro-1-butanesulfonyloxy)-1-napthoate

Perfluoro-1-butanesulfonyl fluoride (19 mL, 106 mmol, 1 eq) was added toa solution of methyl 2-hydroxy-1-naphthoate (21.25 g, 105 mmol, 1 eq)and triethylamine (15 mL, 108 mmol, 1 eq) in tetrahydrofuran (150 mL)maintained at an internal temperature about 0° C., under nitrogen. Oncethe addition was complete, the mixture was allowed to warm to ambienttemperature and stirred for 64 hours. Toluene (150 mL) was added causingsome precipitation. The solids were removed by filtration throughCeliteä and washed with toluene (20 mL). The organic solutions werecombined and washed with 2 N HCl (aq) (2×50 mL), water (100 mL),saturated aqueous sodium carbonate solution (100 mL) and brine (100 mL).The organic layer was dried (MgSO₄), filtered and concentrated underreduced pressure. Yield 48.79 g, 95%

EXAMPLE 1 Methyl 2-diphenylphosphino-1-naphthoate

A stirred solution of methyl 2-trifluoromethanesulfonyloxy-1-naphthoate(52.7 g, 158 mmol, 1 eq), triethylamine (26.5 ml, 190 mmol, 1.2 eq) andpalladium acetate (0.15 g, 0.7 mmol, 0.004 eq) in acetonitrile (600 ml)was sparged with nitrogen for 30 minutes. Diphenylphosphine (29.4 g, 158mmol, 1 eq) was added instantly giving a red coloration. The solutionwas heated at reflux under nitrogen for 17 hours. The blood-red solutionwas allowed to cool and concentrated under reduced pressure toapproximately half its original volume. Methanol (50 ml) was added andthe mixture concentrated a little more under reduced pressure. Theproduct crystallised from this mixture and was collected by filtrationand washed with ice-cold methanol (200 ml) and dried under vacuum atambient temperature; ³¹p NMR (162 mHz; CDCl₃): δ−7.8. Yield 54.1 g, 92%

The product may be converted to a ligand (1) or (2) or the oppositeenantiomer thereof, by known procedures.

EXAMPLE 2 Methyl 2-diphenylphosphino-1-naphthoate from methyl2-(perfluoro-1-butanesulfonyloxy)-1-naphthoate

Diphenylphosphine (0.51 mL g, 2.93 mmol, 1 eq) was added to a stirredsolution of methyl 2-perfluoro-1-butanesulfonyloxy-1-naphthoate (1.431g, 2.95 mmol, 1 eq), triethylamine (0.45 mL, 3.23 mmol, 1.1 eq) andpalladium acetate (0.005 g, 0.02 mmol, 0.007 eq) in degassedacetonitrile (10 mL) instantly giving a red coloration. The solution washeated at reflux under nitrogen for 17 hours. The blood-red solution wasallowed to cool and an aliquot taken for NMR analysis.

³¹P NMR showed complete consumption of diphenylphosphine and formationof substantially one product, the desired triarylphosphine, identical tothat described in Example 1.

EXAMPLE 3 Methyl 2-diphenylphosphino-1-naphthoate (toluene as solvent)

Diphenylphosphine (0.72 mL, 4.14 mmol, 1 eq) was added to a stirredsolution of methyl 2-trifluoromethanesulfonyloxy-1-naphthoate (1.389 g,4.16 mmol, 1 eq), triethylamine (0.64 mL, 4.59 mmol, 1.1 eq) andpalladium acetate (0.005 g, 0.02 mmol, 0.005 eq) in degassed toluene (10mL) instantly giving a red coloration. The solution was heated at refluxunder nitrogen for 17 hours. The blood-red solution was allowed to cooland an aliquot taken for NMR analysis.

31P NMR showed complete consumption of diphenylphosphine and formationof substantially one product, the desired triarylphosphine, identical tothat described in Example 1.

EXAMPLE 4 Methyl 2-diphenylphosphino-1-naphthoate (DMF as solvent)

Diphenylphosphine (0.72 mL, 4.14 mmol, 1 eq) was added to a stirredsolution of methyl 2-trifluoromethanesulfonyloxy-1-naphthoate (1.384 g,4.14 mmol, 1 eq), triethylamine (0.64 mL, 4.59 mmol, 1.1 eq) andpalladium acetate (0.005 g, 0.02 mmol, 0.005 eq) in degassed DMF (10 mL)instantly giving a red coloration. The solution was heated at refluxunder nitrogen for 17 hours. The blood-red solution was allowed to cooland an aliquot taken for NMR analysis.

³¹P NMR showed complete consumption of diphenylphosphine and formationof substantially one product the desired triarylphosphine, identical tothat described in Example 1.

EXAMPLE 5 Methyl 2-Diphenylphosphino-1-naphthoate (DMSO as solvent)

Diphenylphosphine (0.72 mL, 4.14 mmol, 1 eq) was added to a stirredsolution of methyl 2-trifluoromethanesulfonyloxy-1-naphthoate (1.373 g,4.11 mmol, 1 eq), triethylamine (0.64 mL, 4.59 mmol, 1.1 eq) andpalladium acetate (0.005 g, 0.02 mmol, 0.005 eq) in degassed DMSO (10mL) instantly giving a red coloration. The solution was heated at refluxunder nitrogen for 17 hours. The blood-red solution was allowed to cooland an aliquot taken for NMR analysis.

³¹P NMR showed complete consumption of diphenylphosphine and formationof the desired triarylphosphine as the major product, and a secondproduct (ca 25% of mixture), having a chemical shift consistent with theoxide of triarylphosphine, δ (162 MHz, CDCl₃) +31.2.

EXAMPLE 6 Methyl 2-diphenylphosphino-1-naphthoate (acetonitrile assolvent, with 1,4-bis(diphenylphosphino)butane additive)

Diphenylphosphine (0.55 mL, 3.16 mmol, 1 eq) was added to a stirredsolution of methyl 2-trifluoromethanesulfonyloxy-1-naphthoate (1.047 g,3.13 mmol, 1 eq), triethylamine (0. 5 mL, 3.59 mmol, 1.1 eq),1,4-bis(diphenylphosphino)butane (dppb) (0.03 g, 0.07 mmol, 0.02 eq) andpalladium acetate (0.005 g, 0.02 mmol, 0.006 eq) in degassed MeCN (10mL) instantly giving a red coloration. The solution was heated at refluxunder nitrogen for 17 hours. The blood-red solution was allowed to cooland an aliquot taken for NMR analysis.

³¹P NMR showed complete consumption of diphenylphosphine and formationof the desired triarylphosphine as the major product, and a secondproduct (ca 32% of mixture), having a chemical shift consistent with theoxide of triarylphosphine, δ (162 MHz, CDCl₃)+31.2.

EXAMPLE 7 Methyl 2-diphenylphosphinobenzoate

Diphenylphosphine (0.94 mL, 5.40 mmol, 1 eq) was added to a stirredsolution of methyl 2-trifluoromethanesulfonyloxybenzoate (1.531 g, 5.39mmol, 1 eq), triethylamine (0.85 mL, 6.1 mmol, 1.1 eq) and palladiumacetate (0.005 g, 0.02 mmol, 0.004 eq) in degassed MeCN (10 mL)instantly giving a red coloration. The solution was heated at refluxunder nitrogen for 17 hours. The blood-red solution was allowed to cooland an aliquot taken for NMR analysis.

³P NMR showed complete consumption of diphenylphosphine and formation ofsubstantially one product the desired triarylphosphine, δ (162 MHzCDC₃)−3.3.

What is claimed is:
 1. A process for preparation of an arylphosphine ofthe formula R¹OC—Ar—PR²R³ wherein Ar is aryl or heteroaryl; R¹ is analkoxy or amine group, and R² and R³ are each any organic group; andeach of the respective groups may optionally be substituted with anynon-interfering group; which comprises the reaction of a sulfonyloxycompound of the formula R¹OC—Ar—OSO₂R⁴ wherein R⁴ is alkyl, haloalkyl,perhaloalkyl, aryl, aralkyl or alkaryl, with a secondary or primaryphosphine of the formula HPR²R³, in a solvent and in the presence of apalladium catalyst and a base.
 2. The process according to claim 1,wherein the catalyst is a palladium (II) salt.
 3. The process accordingto claim 2, wherein the catalyst is palladium (II) acetate.
 4. Theprocess according to claim 1, wherein the base is a tertiary amine. 5.The process according to claim 4, wherein the base is triethylamine. 6.The process according to claim 1, wherein R² and R³ are each aryl oralkyl.
 7. The process according to claim 6, wherein R² and R³ are eachoptionally substituted phenyl.
 8. The process according to claim 1,wherein Ar bears the COR¹ and OSO₂R⁴ groups in a 1,2-relationship. 9.The process according to claim 1, wherein the sulfonyloxy compound hasthe formula

wherein R is any non-interfering substituent and/or represents a fusedring.
 10. The process according to claim 8, wherein Ar is naphthyl. 11.The process according to claim 1, wherein R¹ is alkoxy.
 12. The processaccording to claim 8, wherein the arylphosphine has the formula


13. The process according to claim 1, wherein R⁴ is perfluoroalkyl. 14.The process according to claim 13, wherein R⁴ is trifluoromethyl. 15.The process according to claim 13, wherein R⁴ is perfluoro-1-butyl. 16.The process according to claim 1, wherein the solvent has a boilingpoint below 125° C.
 17. The process according to claim 16, whichadditionally comprises concentrating the arylphosphine by removal of thesolvent under reduced pressure.
 18. The process according to claim 16,wherein the solvent is an aromatic hydrocarbon.
 19. The processaccording to claim 18, wherein the solvent is toluene.
 20. The processaccording to claim 16, wherein the solvent is acetonitrile.
 21. Theprocess according to claim 1, wherein the reaction mixture issubstantially free of chelating phosphine.
 22. The process according toclaim 1, wherein the catalyst loading is less than 1%.
 23. The processaccording to claim 22, wherein the catalyst loading is less than 0.5%.24. The process according to claim 1, which comprises the additionalstep of converting the arylphosphine to a chiral phosphine ligand. 25.The process according to claim 24, wherein the chiral phosphine ligandis an enantiomerically enriched compound of formula (1) or (2)

or the opposite enantiomer thereof.
 26. The process according to claim11, wherein R¹ is methoxy.
 27. The process according to claim 17,wherein the solvent is an aromatic hydrocarbon.
 28. The processaccording to claim 27, wherein the solvent is toluene.
 29. The processaccording to claim 17, wherein the solvent is acetonitrile.